The overall aim is to explore mechanisms by which hallucinogenic drug, actiong through 5-HT2A receptors, enhance glutamatergic synaptic transmission in the prefrontal cortex. The proposed experiments focus upon how 5-HT2A receptor activation induces two distinct types glutamateric excitatory postsynaptic potentials/currents (EPSPs/EPSCs) at apical dendrites of layer V pyramidal cells of medial prefrontal cortex. The first is a 5-HT-induced increase in spontaneous (non-electrically-evoked) EPSCs that directly or indirectly involves thalamocortical terminals in the midline/intralaminar ascending arousal pathway. The second is a late component of corticocortical electrically-evoked EPSCs, a signature effect of both indoleamine (e.g., LSD) and phenethylamine (e.g., mescaline, DOI) psychedelic hallucingenic drugs. The studies will be conducted with a combination of whole cell patch-clamp recording and 2-photon laser scanning to identify events at a single synapse level; this will be done in conjunction with localized molecular manipulations of 5-HT2 receptor expression. Specific aims are: 1) To determine how 5-HT-induced spontaneous EPSCs (spEPSCs) are generated in layer V pyramidal cells of medial prefrontal cortex and 2) To determine the mechanisms underlying hallucinogen-induced late electrically-evoked EPSCs (evEPSCs) in mPFC layer V pyramidal cells and its modulation by non-5-HT2A and NMDA receptors. Significance: Hyperglutamatergic states have been suggested to underlie both drug-induced psychoses and prodromal stages of naturally occurring psychoses as schizophrenia. The concept that a downstream dysfunction of glutamatergic transmission could be involved in the early pathogenesis of schizophrenia prompts a search for novel therapies that are prophylactic rather than symptomatic as are the traditional monoamine receptor-targeted typical or atypical antipsychotic drugs.